Rabson–Mendenhall Syndrome with Severe Insulin Resistance Type A: The Need to Act Faster than the Disease

Abstract

Introduction Rabson–Mendenhall syndrome (RMS) is an autosomal disorder where severe insulin resistance is observed. Insulin levels decrease over time and suppress gluconeogenesis in the liver. Fatty acid oxidation is affected, leading to frequent episodes of ketoacidosis. The changes in RMS are much faster than in patients with type 2 diabetes. RMS patients have a significantly reduced life expectancy and may die during adolescence or early adulthood.

Case Presentation A 15-year-old girl presented with poorly controlled diabetes. She was diagnosed with RMS at the age of 50 days, and her genetic study showed a homozygous mutation for R141W in the INSR gene. Her insulin level was high at 737 μIU/mL, insulinoma antigen 2 and glutamic acid decarboxylase antibodies were negative, and C-peptide was > 18 ng/mL. There is a strong family history of RMS on her mother's side. Her hyperglycemia was treated with an insulin pump (requiring up to 300 units of insulin/day) and oral rosiglitazone for the first 6 years. Rosiglitazone was replaced by oral insulin-like growth factor 1 (IGF1). Over the last 3 years, she had four further episodes of diabetic ketoacidosis triggered by infections and severe lipodystrophy. A trial of leptin and subcutaneous IGF1 has failed. The patient has a closed-loop insulin pump MiniMed 780G with a total daily dose of 261 units (4.6 U/kg/day).

Results During the past 15 years, the patient suffered many health, psychological, family, and school issues. These issues were due to RMS itself, complications of diabetes, side effects of medications, and technology failure. Our multidisciplinary team tackled all issues by providing the most appropriate care, mediation, and technology.

Conclusion To act faster than the disease progression, we need to know the whole list of issues our patient could face, as this will help us to look at the entire picture rather than treating different pieces separately. Effective cooperation between the teams is crucial and needs to be organized through a family physician or by the team involved the most in patient care. Although technology has limitations, it still helps when used appropriately.

Keywords

insulin resistance type A - Rabson–Mendenhall syndrome - RMS

Introduction

Insulin resistance is one of the most challenging conditions, and it is identified as an unexpected subnormal response to endogenous and/or exogenous insulin. Commonly, insulin resistance is diagnosed in obese patients because of the variable abnormality spectrum of glucose homeostasis, which leads to abnormal glucose metabolism.[1]

Rarely severe insulin resistance is found with genetic syndromes. Abdominal obesity, particularly accompanying insulin resistance on peripheral glucose and fatty acid utilization, leads to type 2 diabetes. While in severe insulin resistance syndromes, patients usually present with hyperglycemia notwithstanding very high doses of insulin due to insulin receptor dysfunction. The insulin resistance secondary to genetic mutations shares a similar clinical picture, and patients with the genetic syndromes characteristically have intense insulin resistance along with some severe phenotypes.[2]

Rabson–Mendenhall syndrome (RMS) is a rare autosomal disorder marked by severe insulin resistance associated with various phenotypic manifestations. A severe insulin-resistant type of diabetes was first reported by Mendenhall in 1950; postmortem hyperplasia of the pineal gland was described in the child.[3] In 1956, Rabson et al identified RMS in three children with familial hypertrophy of the pineal gland and diabetes mellitus.[4] Later in 1975, West et al described two siblings with similar clinical features associated with dysmorphia.[5] Patients with RMS survive early childhood but have a significantly reduced life expectancy and may die during adolescence or early adulthood. However, one case study from Spain reports on long-term survival in a patient with RMS.[6] The changes in RMS are much faster than in patients with type 2 diabetes mellitus.[7]

Case Presentation

We report the case of a 15-year-old female with poorly controlled diabetes. The girl was presented in diabetic ketoacidosis (DKA) at the age of 50 days, and her genetic study showed a homozygous mutation for R141W in the INSR gene, known to cause RMS. A strong family history of RMS in her mother's cousins (one affected and two carriers) was noted.

She was a full-term baby, born by caesarian section with a birth weight of 2.19 kg, and required 10-day admission to the neonatal unit. She was readmitted on day 50 in DKA. Her insulin level was high at 737 μIU/mL, insulinoma antigen 2 and glutamic acid decarboxylase antibodies were negative, and C-peptide was > 18 ng/mL (5.99 nmol/L). After recovery, the patient's blood glucose level was stabilized on a very high dose (200–300 IU/day) of concentrated insulin through continuous subcutaneous insulin infusion (CSII); oral rosiglitazone was added after 2 months. This treatment was continued for 6 years, after which oral mecasermin replaced rosiglitazone.

From 6 to 12 years old, she had four further episodes of DKA associated with acute infections—right lobar pneumonia, cellulitis of the abdominal wall, acute gastroenteritis, and lipohypertrophy, respectively. In each episode, she required high doses of intravenous insulin infusion (up to 5 IU/kg/hour). Her CSII treatment led to the development of severe lipodystrophy at the cannula insertion sites; this has led on two occasions to quick switching of her CSII to multiple daily injection therapy; glargine 300 IU daily, lispro 20 IU three times a day along with mecasermin, and SGLT2 inhibitor. Recently, she had a further two episodes of DKA precipitated by severe methicillin-resistant Staphylococcus aureus septicemia and unnoticed pump failure; it was managed as usual with very high doses of intravenous insulin infusion.

From 2020 to 2021, the patient was on combined therapy of mecasermin 25 units subcutaneously twice daily and oral dapagliflozin 10 mg once daily along with CSII, Medtronic 640 using insulin lispro (the total daily dose is 261 units /day (4.6U/kg/day) with insulin to carbohydrate ratio of 1:3 g, and insulin sensitivity factor of 1:20 mg/dL. A trial of recombinant human leptin was not adequate and was stopped.

Currently, she is being treated with dapagliflozin/metformin 10/1,000 mg tablet (Xigduo) and shifted to CSII hybrid closed-loop system (Medtronic 780G) to improve her glycemic control, insulin resistance, and quality of life. Despite intensified therapy, team, and family support, her glycemic control remains poor, with an average blood glucose of 304 ± 86 mg/dL and hemoglobin A1c of 10.8 ± 1.2%.

Our patient's suffering started soon after birth. However, the problems list has increased and become more complicated over the last 5 years, as summarized in [Table 1].

Table 1 List of all the issues our patient has faced over the last 5 years

Abbreviations: COVID-19, coronavirus disease 2019; DKA, diabetic ketoacidosis; IGF1, insulin-like growth factor 1.

Discussion

Insulin resistance is one of the most serious issues RMS patients face; therefore, glycemic control is a challenging process in the management course of these patients. A mutation in the INSR gene causes severe compromise of insulin receptor (INSR) function in RMS. An interaction between insulin and insulin-like growth factor 1 (IGF1) receptors causes a noticeable delay in linear growth and failure to thrive. The patient presented with high fasting and post prandial blood glucose level despite the very high insulin; this can be explained by the improper hepatic insulin clearance or hepatic steatosis in patients with RMS due to INSR dysfunction.[8]

This patient was tried on so many medications to reduce insulin resistance, and most of the medications failed, although each time, the failure was related to the ineffectiveness of the medication. However, compliance issues could not be ruled out.

Frequent hospital visits due to multiple issues and requiring different specialties and subspecialties were a considerable burden to the family, requiring a lot of time, money, and effort. Our team tried to reduce this burden by combining five to six specialties' appointments on the same day. Pump clinic multidisciplinary team (MDT) room in where (in The Imperial College London Diabetes Centre- Abu Dhabi) the endocrinologist, dietician, diabetes educator, and psychologist sat next to each other, while the nephrologist, cardiologist, retinal camera examination, and ophthalmologist were in the same building. The school nurse was contacted regularly by our diabetes educators, and issues were discussed with the patients and parents in our pump MDT clinic.

Another issue faced by our patient was the systemic development of lipohypertrophy and high consumption of pump accessories due to high insulin volume requirement. We have tried to reduce the insulin valium used by this patient (hence, reducing lipohypertrophy and consumption of pump accessories) by using concentrated insulin. However, after discussing the idea with the pump technology team, this was not possible due to safety issues, and our request was passed to the team dealing with the pump logarithm. The technology team may need to improve their pumps' algorithm to suit patients requiring concentrated insulin. The insurance team was approached, the consumption of insulin and pump consumables was discussed, and we managed to get the approval process easier and faster. Our nurses were instructed to take extra blood samples each time we needed to do annual review blood tests, and the mother was asked to check her subsequent appointments with other specialties if any blood test was needed to avoid unnecessary frequent pricks.

Despite the initial resistance of the patient and her mother to see a psychologist, consent to refer the patient to our psychologist was obtained, and our psychologist and psychiatrist dealt with all psychological issues.

RMS patients have a significantly reduced life expectancy and may die during adolescence or early adulthood. However, increasing awareness among health care professionals and providing the best available treatment may improve these patients' long-term survival and quality of life. The lack of a control group is the main limitation of the study. Therefore, further research on the management of RSM patients is required.

Conclusion

Although RMS is very rare, however, its management is very challenging. Life expectancy is short, with early mortality due to diabetes-related complications resulting from severe insulin resistance and poor glycemic control.

Knowing the list of the expected issues RMS patients could face helps us look at the entire issues of the patient and her family. This allows us to think ahead and act faster than the disease. Effective communication and cooperation between the teams is the key to success.

Advanced technology (like a closed-loop insulin pump) may make a difference. Patient compliance is essential when trying medications like leptin and IGF1 to improve insulin sensitivity and reduce hyperinsulinemia. Successful management of insulin resistance type A requires considering the patient's and family's situation. Further research on the management of RSM patients is required.

Conflict of Interest

None declared.

Patient Consent

The authors confirm that the manuscript was submitted to the journal with the patient's and her mother's permission.

Compliance with Ethical Principles

No ethical approval is required for single case reports.

Authors' Contributions

All named authors are involved in the patient's care and contributed substantially to the manuscript's conceptualization, data collection, drafting, and finalization.

• References

• 1 Krentz AJ. Insulin Resistance: A Clinical Handbook. United Kingdom: Southampton University Hospitals; 2008
• 2 Melvin A, O'Rahilly S, Savage DB. Genetic syndromes of severe insulin resistance. Curr Opin Genet Dev 2018; 50: 60-67
• 3 Ando A. Rabson-Mendenhall syndrome [in Japanese]. Jpn J Clin Med 1994; 52 (10) 2641-2642
• 4 Rabson SM, Mendenhall EN. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. Am J Clin Pathol 1956; 26 (03) 283-290
• 5 West RJ, Lloyd JK, Turner WM. Familial insulin-resistant diabetes, multiple somatic anomalies, and pineal hyperplasia. Arch Dis Child 1975; 50 (09) 703-708
• 6 Musso C, Cochran E, Moran SA. et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 2004; 83 (04) 209-222
• 7 Hassan I, Altaf H, Yaseen A. Rabson-Mendenhall syndrome. Indian J Dermatol 2014; 59 (06) 633
• 8 Gosavi S, Sangamesh S, Ananda Rao A, Patel S, Hodigere VC. Insulin, insulin everywhere: a rare case report of Rabson-Mendenhall syndrome. Cureus 2021; 13 (02) e13126

Publication History

Article published online:
15 September 2023